Project Summary We propose a longitudinal, prospective cohort study to determine if changes in cannabis use frequency are associated with changes in frequency of opioid use and drug-use related health outcomes among opioid- using (both heroin and prescription opiates) people who inject drugs (PWID) in two states with legal adult cannabis sales and use. State-level legalization of adult cannabis sales and use is likely to lead to greater cannabis use and cannabis-related health problems among vulnerable populations. However, increases in cannabis sales and use might have unanticipated consequences for PWID. Preliminary studies suggest substitution of cannabis for opioids among medicinal cannabis patients and community recruited PWID. Ecological studies have found that medical marijuana legalization is associated with lower rates of opioid- related overdose and hospitalization, outcomes that might be observable for legal adult use cannabis. Based on these findings, we theorize that cannabis use may reduce opioid use and thereby lower the risk for opioid- related drug harms such as nonfatal overdose events. Therefore, we propose the following aims: AIM 1: To determine whether changes in cannabis use are associated with changes in frequency of opioid use among opioid-using PWID while adjusting for confounders. Hypothesis 1 (H1): The rate of change in cannabis use over time will be inversely associated with the rate of change in opioid use during the same period. AIM 2: To determine whether changes in cannabis use among opioid-using PWID is associated with changes in non-fatal overdose events while adjusting for confounders. H2: The rate of change in cannabis use will be inversely associated with the rate of change in the number of non-fatal overdose events. To achieve these aims, we propose to recruit, interview, and follow at baseline, 6 and 12 months a prospective, longitudinal cohort of 1,000 opioid-using PWID in Denver, CO (N=500) and Los Angeles, CA (N=500). Opioid-using PWID will be recruited using targeted sampling methods. Multiple observation periods and large sample size will permit the use of cutting edge statistical techniques such as latent growth modelling and finite mixture modelling to rigorously test our hypotheses. Our two sites allow us to observe drug use patterns and health outcomes among racially/ethnically diverse PWID. The prevalence of non-fatal overdoses has increased in recent years. In our 2016/17 sample of Los Angeles PWID (n=472), 21% reported a non-fatal overdose in the last 6 months, meaning the proposed sample should have sufficient non-fatal overdoses events to permit statistical analyses of changes over time as proposed here. Findings will advance drug use epidemiology and may inform new prevention programs for the reduction of drug-related harms. Our study team is multidisciplinary (economics [Pacula], epidemiology [Corsi, Kral], psychology [Booth & Huh], and sociology [Bluthenthal]) and well-prepared to conduct this significant, innovative, and rigorous 4-year research project.